Endocrine disrupter modulation of SXR in development and lymphomagenesis

描述(由申请人提供)： 这是一个R01应用程序，旨在测试类固醇功能丧失和 异种生物受体，SXR，将导致接触者发生淋巴瘤和白血病。确定SXR在人类常见恶性肿瘤中的作用将直接将环境暴露与癌症联系起来，因为SXR可被各种药物和环境化学品激活或拮抗。提出了三个具体的目标：(1)SXR功能丧失如何导致B-1细胞的增殖？(2)化学拮抗剂抑制SXR是否导致B-1细胞和淋巴瘤的增殖增加？(3)在B-1细胞增殖的发育调控中，SXR何时需要采取行动？我们的研究将在SXR功能丧失和淋巴癌之间建立联系，阐明我们对暴露于多氯联苯等环境化学品如何改变基因表达以增加淋巴瘤和白血病风险的理解。因此，确定SXR在常见人类恶性肿瘤中的作用直接将环境暴露与癌症联系起来。暴露于内分泌干扰物对人群来说是一个持续的风险；因此，这些实验将有助于阐明这些与环境相关的SXR调节剂导致淋巴瘤的机制。这些知识将有助于指导和集中今后的预防工作。创新拟议的研究具有创新性，因为据我们所知，还没有人提供机制上的联系，说明环境中暴露于多氯联苯和多溴二苯醚等有机卤素化合物与非霍奇金淋巴瘤(NHL)等血癌之间的联系。我们发表的研究将SXR功能丧失与NF-κB过度活跃和慢性炎症联系在一起，最近我们发现SXR功能丧失会导致小鼠发生B-1a B细胞淋巴瘤。我们采用了一种创新的小鼠模型，人源化SXR敲入(HSXRki)，它在内源性小鼠启动子的控制下在全身表达人SXR。这一模型允许我们检验新的假设，即在体内，化学拮抗剂抑制SXR功能会导致淋巴增殖和淋巴瘤。

DESCRIPTION (provided by applicant): This is an R01 application intended to test the hypothesis that loss-of-function in the steroid and xenobiotic receptor, SXR, will lead to lymphoma and leukemia in exposed individuals. Establishing a role for SXR in common human malignancies will directly link environmental exposures and cancer because SXR is activated or antagonized by a variety of drugs and environmental chemicals. Three specific aims are proposed: (1) How does SXR loss-of-function lead to proliferation of B-1cells?, (2) Does inhibition of SXR by chemical antagonists lead to increased proliferation of B-1 cells and lymphoma?, (3) When is SXR action required in the developmental regulation of B-1 cell proliferation? Our studies will forge a link between SXR loss-of-function and lymphatic cancers, illuminating our understanding of how exposure to environmental chemicals such as PCBs alters gene expression to increase the risk of lymphoma and leukemia. Therefore, establishing a role for SXR in common human malignancies directly links environmental exposures and cancer. Exposure to endocrine disrupting chemicals is a continuing risk to the population; hence, these experiments will aid in elucidating a mechanism through which these environmentally relevant SXR modulators contribute to lymphomas. This knowledge will help to guide and focus future prevention efforts. Innovation The proposed research is innovative in that, to our knowledge, no one has yet provided a mechanistic link for how environmental exposures to organohalogen compounds such as PCBs and PBDEs are linked to blood cancers such as non-Hodgkin's lymphoma (NHL). Our published studies link SXR loss-of-function with NF-κB hyperactivity and chronic inflammation and we recently showed that SXR loss-of-function leads to a B-1a B cell lymphoma in mice. We employ an innovative mouse model, the humanized SXR knock-in (hSXRki) that expresses human SXR throughout the body under the control of the endogenous mouse promoter. This model allows us to test the novel hypothesis that inhibition of SXR function by chemical antagonists, in vivo, leads to lymphoproliferation and lymphoma.